Endometriosis is one of the most common gynaecological disorders, affecting 10 to 15% of women in the reproductive age. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity, and is most frequently found in the pelvic area. In women developing endometriosis, these endometrial cells have the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow. It is not known yet why some women develop endometriosis and others do not. The implants respond to the menstrual cycle in a similar way as the endometrium in the uterus. However, infiltrating lesions and the blood from these lesions, unable to leave the body, cause inflammation of the surrounding tissue. The most common symptoms of endometriosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions. Some women with severe endometriosis are asymptomatic, while women with mild endometriosis may have severe pain.
Until now, no non-invasive test is available to diagnose endometriosis. Laparoscopy has to be performed to diagnose the disease. Endometriosis is classified according to the 4 stages set up by the American Fertility Society (AFS). Stage I corresponds to minimal disease while stage IV is severe, depending on the location and the extent of the endometriosis.
Endometriosis is found in up to 50% of the women with infertility. However, currently no causal relation is known to exist between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility.
Despite extensive research, the cause of endometriosis is still largely unknown. Several theories for the origin of endometriosis have been proposed, although no single hypothesis explains all cases of the disease completely. However, the key event in all these theories is the occurrence of retrograde menstruation.
The aims of treatment of endometriosis are pain relief, resolution of the endometriotic tissue and restoration of fertility (if desired). The two common treatments are surgery or hormonal therapy or a combination of both.
Surgical treatment removes the endometriotic tissue. Initially, the pain relief using this procedure approaches 70-80%. However, the pain returns in a lot of cases because of re-growth of the endometriotic tissue. At present the most permanent way to treat endometriosis is the removal of the ovaries, thus eliminating the production of estrogens and possible other ovarian factors, which regulate the growth and activity of the endometriotic tissue.
The currently available pharmacological treatments of endometriosis are anti-inflammatory and hormonal. In the early stages of endometriosis non-steroidal anti-inflammatory drugs (NSAID's) are often successful in relieving the pelvic pain. Hormonal treatment is given mainly to down-regulate the estrogen production by the ovaries. Various drugs are available for suppressing this ovarian function as will be explained below.
Danazol and gestrinone are both testosterone-derivatives, suppressing the pituitary release of follicle stimulating hormone (FSH) and luteinising hormone (LH). The efficacy of these two drugs on the regression of endometriotic tissue is no better than that of other hormonal treatments. However, both these drugs have pronounced androgenic side effects, like weight gain, acne and hirsutism, which explains the diminishing popularity of these drugs. In addition, these drugs produce a hypoestrogenic milieu.
Gonadotrophin releasing hormone (GnRH) agonists (e.g. nafareline, busereline) give a more complete suppression of the ovarian activity, leading to down-regulation of LH and FSH receptors. However, this inactivity of the ovaries does not result in disappearance of the endometriosis. Several comparative randomised studies have shown that the efficacy of these drugs is no better than that of other existing hormonal treatments. The use of GnRH agonists is limited because the women taking these drugs develop hypoestrogenic symptoms, such as hot flushes, sweating, headache, vaginal dryness, and decrease in bone mineral density (BMD). Therefore these drugs can only be administered for a maximal period of approximately 6 months. Add-back therapy (suppletion of low doses of an estrogen, an estrogen with a progestogen or a progestogen with estrogenic activity) is sometimes given to women receiving GnRH agonists, to diminish the hypoestrogenic symptoms. However, it still has to be proven if treatment with GnRH agonists and add-back therapy for more than 6 months without unwanted side effects is possible and if such a treatment remains effective against endometriosis throughout said period.
Progestogens have been used in a wide range of pharmaceutical applications for decades, including endometriosis. These drugs also work by suppressing LH and FSH and consequently induce hypoestrogenism. Examples of progestogens given for endometriosis are medroxyprogesterone acetate, dydrogesterone and lynestrenol. These drugs are also associated with side-effects e.g. mood changes and breakthrough bleedings. The treatment of endometriosis with progestogens has not received regulatory approval in the United States.
Oral contraceptives, containing both an estrogen and progestogen, are also prescribed for endometriosis. However, this treatment is not optimal, because the stimulatory effect of the estrogenic compound in the endometriotic lesions may not be counteracted effectively enough by the progestogen and because the withdrawal bleeding induced also causes bleeding in endometriotic tissue.
A large percentage of women experience relief of symptoms while being treated with the above hormonal drugs. However, symptom recurrence is likely once the drug is discontinued. None of the aforementioned drugs is suitable for long term treatment of endometriosis, because of the severe side-effects which are largely associated with hypoestrogenism. These treatments are therefore in most cases discontinued after a period of 6 months after which recurrence of the symptoms is likely to occur.
It will be evident from the above that there is a great need for a pharmaceutical treatment of endometriosis, which treatment may be applied for a longer period of time than the existing hormonal treatments, preferably until such time that the treated female reaches menopause, and/or which treatment produces better results, particularly in terms of side-effects during treatment and recurrence rate after discontinuation of the therapy. Everything that has been said above in relation to the treatment of endometriosis equally applies to other benign estrogen sensitive gynaecological disorders, notably adenomyosis, uterine fibroids, dysmenorrhoea, menorrhagia and metrorrhagia. These benign gynaecological disorders are all estrogen sensitive and treated in a comparable way as described herein before in relation to endometriosis. The available pharmaceutical treatments, however, suffer from the same major drawbacks as mentioned in connection with endometriosis, i.e. they have to be discontinued once the side-effects become more serious than the symptoms to be treated and/or symptoms reappear after discontinuation of the therapy.